- Preparation method of isoquinolinone compound
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The invention relates to a preparation method of an isoquinolinone compound. Specifically, the method for preparing the compound shown in the formula 2 comprises the step that a compound shown in a formula b reacts with a methylation reagent to obtain the compound shown in the formula 2. The method provided by the invention is used for preparing the isoquinolinone compound (such as Roxadustat), and has the excellent effects of reasonable route, convenience, feasibility, high yield, high purity, suitability for industrial production and the like.
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Paragraph 0297-0301
(2021/07/17)
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- Preparation method of roxadustat intermediate
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The invention discloses a preparation method of a roxadustat intermediate. The method comprises the following steps: anhydride ring opening, esterification, ring closing, aromatization, deprotection, chlorination and methylation to obtain the roxadustat intermediate. According to the invention, the preparation method provided by the invention makes full use of the atom economy theory, is easy to operate, low in cost and low in pollution, and is suitable for large-scale industrial production; and only one-time refining is carried out, the chromatographic purity can reach 99.5% or above, and the total yield of the six-step reaction is 30% or above.
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- PROCESS OF MAKING ROXADUSTAT
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The invention relates to a method of manufacturing roxadustat of formula (I), comprising the conversion of a compound of formula (VI) to roxadustat, R being an alkyl group in C1- C20 and PG being a protective group.
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Paragraph 0042
(2021/12/30)
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- A General Organocatalytic System for Electron Donor-Acceptor Complex Photoactivation and Its Use in Radical Processes
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We report herein a modular class of organic catalysts that, acting as donors, can readily form photoactive electron donor-acceptor (EDA) complexes with a variety of radical precursors. Excitation with visible light generates open-shell intermediates under mild conditions, including nonstabilized carbon radicals and nitrogen-centered radicals. The modular nature of the commercially available xanthogenate and dithiocarbamate anion organocatalysts offers a versatile EDA complex catalytic platform for developing mechanistically distinct radical reactions, encompassing redox-neutral and net-reductive processes. Mechanistic investigations, by means of quantum yield determination, established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts' stability and the method's high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups, including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and enantioselective radical catalysis.
- De Pedro Beato, Eduardo,Melchiorre, Paolo,Spinnato, Davide,Zhou, Wei
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supporting information
p. 12304 - 12314
(2021/08/20)
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- Method suitable for industrial production of roxadustat intermediate
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The invention discloses a preparation method of a roxadustat intermediate. 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylic ester (IV) is a key intermediate for preparing roxadustat. The preparation method comprises the steps of (1) reacting a compound I and a compound II in an organic solvent under the catalysis of acid to prepare an intermediate III; and (2) carrying out cyclization reaction on the intermediate III in an organic solvent and a catalytic system to prepare the roxadustat intermediate IV. The preparation method of the roxadustat intermediate has the advantages that the raw materials are easy to obtain, the operation steps are few, the process is simple, the reaction yield is high, the atom utilization rate is high, and industrial production is easy.
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Paragraph 0064-0067
(2021/09/04)
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- Preparation method of isoquinoline derivative
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Disclosed is a preparation method of an isoquinoline derivative. A preparation method of a compound represented by a general formula II, i.e., 4-hydroxy-1-methyl-7-phenoxy isoquinoline-3-formate, is provided, wherein substituent definitions are as defined in the specification. The preparation method comprises the following steps of: under an acidic condition, dissolving a compound shown as a structural formula III in dimethyl sulfoxide, catalyzing by a ferrous ion (Fe) catalyst, and oxidizing by H2O2 to obtain the 4-hydroxy-1-methyl- 7-phenoxy isoquinoline-3-formate shown as the structuralformula II. By using the method, the production efficiency can be greatly improved, the production cost is reduced, the product purity can be ensured, and the method is suitable for industrial mass production.
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- Preparation method of roxadustat intermediate
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The invention discloses a preparation method of a roxadustat intermediate, which comprises the following steps of: firstly, reacting methyl nitroacetate with trimethyl orthoformate to obtain a product I, and performing catalytic hydrogenation reduction to obtain a product II; then reacting the product II with m-phenoxyacetophenone to obtain a product III; carrying out a Pomeranz-Fritsch reaction on the product III, and completing intramolecular ring closing to obtain a product IV; finally, carrying out an oxidation reaction on the product IV to obtain the roxadustat intermediate 1-methyl-4-hydroxy-7-phenoxy isoquinoline-3-methyl carboxylate. According to the preparation method of the roxadustat intermediate, the raw materials are easy to obtain, and the production cost can be remarkably reduced. The whole process is simple, the whole consumed time is short, the production efficiency is high, the yield is high, the reaction condition is mild, the post-treatment is simple and convenient, and the method is suitable for large-scale preparation and has a great application prospect.
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Paragraph 0081-0092
(2021/07/08)
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- Preparation method of bleomycin
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The invention discloses a preparation method of Roxadustat, compound 1 and bis(dimethylamino)methane are heated in a mixed solvent of acetic acid and trifluoroacetic acid for reaction to form compound2; acetic anhydride is added to the obtained reaction solution of the compound 2 for completing reaction by heating to form compound 3; the compound 3 is dissolved in ethyl acetate and heated, then is catalyzed by Pd/C, and reduced by hydrogen to obtain compound 4; the compound 4 and glycine are dissolved in a solvent, and heated under the action of an organic base for reaction to obtain compound5; wherein the solvent is one or more of dioxane, ethylene glycol monomethyl ether, toluene, acetonitrile and n-propanol, the organic base is one or more of triethylamine, 1,8-diazabicyclo undecane-7-ene, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and ethylenediamine; the preparation method has the advantages of shorter reaction time, low reaction temperature, low equipment condition requirements and high crude product purity, is suitable for large-scale industrial production, and has a good industrialization prospect.
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Paragraph 0027; 0034-0036; 0040; 0045-0047
(2021/04/07)
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- Preparation method of rosastat key intermediate
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The invention provides a preparation method of a rosastat key intermediate. The intermediate I is 4-hydroxy-1-methyl-7-phenoxy isoquinoline-3-carboxylic ester. The preparation method comprises the following steps: with tyrosine as an initial raw material, sequentially carrying out esterification, acylation, etherification, cyclization, aromatization and oxidation rearrangement reaction to preparethe rosastat key intermediate. The preparation method has the advantages of cheap and easily available raw materials, environmental protection, avoiding of use of phosphorus oxychloride, polyphosphoric acid and other environmentally unfriendly reagents in the cyclization reaction, simple process, simple operation and mild reaction conditions; and the method has the advantages of less three wastesand higher product yield and purity, and is suitable for industrial production.
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- Preparation method of roxadustat intermediate
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The invention discloses a preparation method of a roxadustat intermediate, belonging to the technical field of medicine preparation. The preparation method comprises the following steps: preparing 2-acetamido-3-oxo-3-(4-phenoxyphenyl)propionate from 3-oxo-3-(4-phenoxyphenyl)propionate, and then performing a cyclization reaction to obtain 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate. The method is novel in route and short in synthesis route; all the used raw materials and reagents are easy to obtain or prepare; reagents with high risk and high pollution are not used; the method is safe and environmentally friendly, and is mild in reaction conditions and convenient and controllable to operate; and the prepared roxadustat intermediate is good in purity, high in yield, obvious in cost advantage and suitable for industrial production.
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Paragraph 0051-0053; 0059-0060
(2020/08/22)
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- Preparation method of Roxadustat intermediate
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The invention provides a preparation method of a Roxadustat intermediate, and particularly relates to a preparation method of a Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. The preparation method comprises the following steps: carrying out a halogenation reaction on 4-hydroxy-1-hydrogen-7-phenoxy-3-isoquinoline carboxylate and a halogenating agent in the presence of a solvent to prepare 4-hydroxy-1-chloro/bromo/iodine-7-phenoxy-3-isoquinoline carboxylate, and further carrying out a methylation reaction in the presence of a catalyst, an alkali and a solvent to prepare 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline carboxylate. The preparation method provided by the invention has the advantages of easily available raw materials, mature and controllable process route and high reaction yield so as to be beneficial to industrial production of bulk drugs.
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Paragraph 0070-0071; 0073; 0075-0076
(2020/04/02)
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- Preparation method of roxadustat
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The invention relates to a preparation method of roxadustat. In the method, methyl 4-hydroxy-7-phenoxyisoquinoline-3-formate and N,N,N',N'-tetramethyldiaminomethane as raw materials are reacted in glacial acetic acid and methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is obtained after the reaction is finished; the obtained methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is dissolved into glacial acetic acid, zinc is added, diluted hydrochloric acid is added, and after the reaction is finished, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is obtained; the obtained methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is mixed with glycine, and dissolved into methanol, sodium methoxide is added, and after the reaction is finished, the target product roxadustat is obtained. The method is mild in reaction condition, simple and controllable in operation, low in preparation cost and suitable for large-scale industrial production, the obtained target product is high in purity, and the production requirements of enterprises are met.
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Paragraph 0035-0044
(2020/08/25)
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- Preparation method of isoquinolinone compound
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The invention provides a preparation method of an isoquinolinone compound, which creatively uses a condensation agent composition of HOBT-EDCI in a specific ratio and the optimal acid binding agent dosage, so that the yield of a compound F is improved; and the reaction solvent is a dichloromethane-water mixture, so that after the reaction is finished, the high-purity compound F can be obtained only by standing and layering a reaction solution and then spin-drying an organic layer. According to the method, complex post-treatment steps in the prior art are avoided and the layered water layer canbe continuously used for preparing the compound F, so that materials are greatly saved, the production operation is facilitated, the economic cost is reduced, and the environmental pollution is reduced. Besides, in the preparation process of the compound C, tetramethyl ethylenediamine is skillfully used, so that the yield of the compound C is greatly improved compared with that in the prior art.
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Paragraph 0059-0062
(2019/07/16)
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- Preparation method of Roxadustat intermediate
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The invention discloses a preparation method of a Roxadustat intermediate (A). The method is characterized in that synthesis routes are defined in the description. The method is simple in process, economical and environmentally friendly, thionyl chloride
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Paragraph 0036; 0046; 0059-0061
(2019/06/12)
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- Preparation method of drug for chronic anemia
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The invention discloses a synthesis method for a drug Roxadustat for chronic anemia. The synthesis method comprises the following steps: hydrolyzing and acidifying a compound shown as a formula 6 under the action of alkali to obtain a key intermediate compound shown as a formula 7; carrying out condensation reaction on the compound shown as the formula 7 and carbonyl diimidazole under suitable conditions to obtain an intermediate compound shown as a formula 8, and separating or not separating the compound shown as the formula 8 from a system to directly take part in subsequent reaction; and finally, reacting the product with glycine to obtain a final product Roxadustat shown as a formula 9. The preparation method has the advantages that the route efficiency is improved, the process cost isreduced, side products are reduced and the purity of a final product is favorably improved (The formula is shown in the description), wherein R2 in the compound shown as the formula 6 represents alkyl, and includes but not limited to methyl, ethyl, isopropyl, tertiary butyl or benzyl.
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- Synthetic method of roxadustat and intermediate compounds of roxadustat
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The invention provides a synthetic method of roxadustat. The synthetic method comprises the following steps: 2-bromo-4-methylfluorobenzoate is taken as a raw material, and the raw material reacts withphenol, butyl vinyl ether, acid and hydroxylamine, and
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Sheet 0055; 0056; 0058; 0059
(2018/12/05)
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- A [...] his preparation method (by machine translation)
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The invention discloses a method for preparing [...] he, [...] he the chemical name is N - [(4 - hydroxy - 1 - methyl - 7 - phenoxy - 3 - isoquinoline) carbonyl] glycine; the process of the invention has simple process, raw materials are easy, economic and environmental protection, help to realize industrialization, [...] he raw material can promote the economic and technological development, and reduces the production cost, high yield, low environmental pollution, is suitable for mass production. (by machine translation)
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- Isoquinolone compound and application thereof
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The invention relates to an isoquinolone compound and application thereof. The invention in particular relates to an isoquinolone compound used as a HIF prolyl hydroxylase inhibitor (HIF-PHI) and a pharmaceutical composition thereof. Moreover, the present invention provides the application of the isoquinolinone compound or the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating HIF-associated or HIF-mediated diseases as anemia or ischemia, local ischemia or hypoxia.
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Paragraph 0199; 0200; 0211-0212
(2018/09/08)
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- CRYSTAL TYPES OF COMPOUNDS INHIBITING ACTIVITY OF PROLYL HYDROXYLASE AND USE THEREOF
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The invention relates to crystal types of compound shown as structural formula I, methods of preparing the compound, intermediate, pharmaceutical composition, and use of treating disease or pharmaceutical preparations for treating disease.
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- Method for preparing Roxadustat intermediate
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The invention provides a preparation method of Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (IV), comprising the step of subjecting 2-(1-(3-phenoxyphenyl)ethylimide)dimalonate (III) as a starting material to condensation and cyclization. The preparation method of the Roxadustat intermediate IV has the advantages that material is easy to obtain, operating steps are few, the process is simple, the reaction yield is high, atom utilization rate is high, and the method is easy for industrial production. The reaction general formula is shown in the specification.
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- Preparation method for intermediate of Roxadustat
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The invention provides a preparation method for an intermediate VI of Roxadustat. The preparation method comprises the following steps: reacting 3-methyl-5-bromoisobenzofuran-1(3H)-one (I), which serves as a starting raw material, with phenol so as to prepare an intermediate II, then, subjecting the II to a ring-opening substitution reaction so as to prepare a compound III, and subjecting the compound III to a substitution reaction so as to prepare a key intermediate V; and subjecting the V to alkali condensation, deprotection and aromatization, thereby preparing the target intermediate VI. The preparation method for the intermediate VI of the Roxadustat, provided by the invention, has the advantages that the raw materials are readily available, the process is simple, the operation is convenient, the reaction yield is high, the atom utilization ratio is high, and the industrial production is facilitated. The reaction general formula is represented by the formulae shown in the description.
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- A substituted heteroaryl compounds and compositions containing such compounds and use thereof (by machine translation)
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The present invention provides a substituted heteroaryl compounds and compositions containing such compounds and its use, the invention discloses a formula (I) indicated by the heteroaryl compound, or its crystalline form, a pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or compound solvent. The invention of monocyclic the base states compounds and compositions containing such compounds may be used to modulate hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO), but also has good pharmacokinetic parameter characteristic, can improve the compound in animal drug concentration, in order to improve the effect of drugs and safety. (by machine translation)
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- POLYMORPHIC FORMS OF COMPOUNDS AS PROLYL HYDROXYLASE INHIBITOR, AND USES THEREOF
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The present invention relates to the polymorphic forms of the compound of Formula (I), preparation thereof including the preparation of intermediates and pharmaceutical compositions, and use of a polymorph above in the treatment of a disease, a disorder o
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- PROCESS FOR MAKING ISOQUINOLINE COMPOUNDS
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The present invention relates to methods for making isoquinoline compounds and the intermediate compounds achieved thereby. Such compounds can be used to prepare compounds and compositions capable of decreasing HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF).
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- POLYMORPHIC FORMS OF COMPOUNDS AS PROLYL HYDROXYLASE INHIBITOR, AND USES THEREOF
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The present invention relates to the polymorphic forms of the compound of Formula (I), preparation thereof including the preparation of intermediates and pharmaceutical compositions, and use of a polymorph above in the treatment of a disease, a disorder o
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- 4 -HYDROXY- ISOQUINOLINE COMPOUNDS AS HIF HYDROXYLASE INHIBITORS
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The present invention relates to novel compounds of formula (I), and compositions capable of inhibiting PHD1 enzyme activity selectively over other isoforms, for example, PHD2 and/or PHD3 enzymes. The invention also relates to compounds of formula (I) for use in disorders such as muscle degeneration, colitis, IBD, and certain ischemias.
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